This project made progress in three research areas during the past year. In the first, we studied the functions of the perirhinal cortex. In collaboration with Barry Richmond and others in the NIMH IRP, we used a recombinant DNA technique to investigate the role of dopamine D2 receptors in perirhinal cortex. We injected a DNA construct that significantly decreased D2 receptor ligand binding and found that the D2 receptor is essential for learning to relate the visual cues to reward schedules (Liu, Richmond, Murray et al., 2004). When schedules of several operant trials must be successfully completed in order to obtain a reward, subjects quickly learn to adjust their behavioral performance using visual cues that signal how many trials remain until reward. Bilateral perirhinal cortex ablations (which include entorhinal cortex) irreversibly prevent this learning. In Liu et al. (2004), we showed that decreasing the D2 receptor in these cortical areas temporarily produced the same learning deficit seen after ablations. The subjects recovered in 2?5 months. This work shows that the D2 receptor in perirhinal cortex is essential for learning to relate the objects to reward schedules. This targeted molecular approach to probing brain function promises to usher in a new era of neuropsychological research, one that will allows much more fine-grained manipulations of neural systems. Combined with increasingly sophisticated behavioral methods, this work represents a major advance in both the understanding of the perirhinal cortex and the methodology of neuropsychology. Furthermore, this approach could be generalized to relate molecular mechanisms to many other cognitive functions. In further studies of the perirhinal cortex, we found, contrary to the prevailing view of medial temporal lobe (MTL) function, that damage to each part of the MTL causes a unique set of behavioral deficits, some involving memory, others involving perception, and yet others involving response selection (reviewed in Murray and Wise, 2004). The empirical neuropsychological evidence favors the idea of diverse functions for the diverse structures making up the MTL, as do some new concepts in neuroanatomy. In collaboration with a research group at the University of Cambridge, we found that human MTL subserves both perceptual and mnemonic functions, with the hippocampus and perirhinal cortex playing distinct roles in spatial and object discrimination, respectively (Lee, Bussey, Murray et al., 2005; Murray, Graham, and Gaffan, 2005). Lesions in perirhinal cortex compromise the representation of visual stimuli, and both accurate perception and accurate memory require these uncompromised perirhinal representations. Thus, the prevailing view that ?perceptual? and ?mnemonic? functions are segregated in the brain can be rejected. In further research pointing to the same conclusions, we showed that perirhinal cortex contributes to the solution of complex visual discriminations with a high degree of ?feature ambiguity? (Bussey, Saksida, and Murray, 2005). In the second line of research continued in the past year, we studied the role of the amygdala and orbitofrontal cortex in affect and learning (Izquierdo and Murray, 2004; Izquierdo, Suda, and Murray, 2004, 2005). We found that unilateral lesions of the amygdala-orbitofrontal cortex circuit disrupt affective processing, that the orbitofrontal cortex is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object-reversal learning), that amygdala lesions facilitated the extinction of instrumental responses, and that lesions of the orbitofrontal cortex had the opposite effect. In addition, we found that subjects can master the reversed-contingency task (Murray, Kralik, and Wise, 2005), but orbitofrontal lesions do not affect this aspect of inhibitory control. In the third line of research continued in Fiscal Year 2005, we studied the role of the hippocampus in both spatial and nonspatial learning. We found that subjects with selective hippocampal lesions can remember the locations of food items, but not when they saw those items (Hampton, Hampstead, and Murray, 2004, 2005). We also found that fornix transection causes a long-lasting impairment in associative learning for nonspatial stimuli and actions, which suggests a general role in the rapid acquisition of associative knowledge, that significant one-trial learning of nonspatial associations depends on the fornix, and that errors made prior to the first correct response retarded one-trial learning, thus supporting the concept of errorless learning (Brasted, Bussey, Murray, and Wise, 2005). In additional work in the past year, we explained the value of neuropsychological methodologies to contemporary neuroscience (Murray and Baxter, 2005) and showed that subjects use prospective memory in the formation of ?learning set,? a term for the ability to improve at learning (Murray and Gaffan, 2005).